PROJECT SUMMARY The proposed phase 2 multicenter study will evaluate the small molecule selective CDK2/cyclin E inhibitor seliciclib in patients with Cushing disease. This rare disease, with an estimated prevalence in the United States of approximately 20,000 cases, results from an adrenocorticotrophic hormone (ACTH)-secreting pituitary corticotroph adenoma and predisposes patients to serious morbidities and increased mortality, mostly due to cardiovascular complications. The current multimodal standard of care of surgical, radiotherapeutic, and medical treatments for this endogenous hypercortisolism is usually not sufficient to control disease, and can lead to serious sequelae. There is a clear unmet need for a medical therapy that directly suppresses pituitary corticotroph ACTH secretion and normalizes cortisol levels in patients with this rare disease. Preclinical discoveries led to identification of seliciclib (R-roscovitine), which directly targets processes promoting ACTH overproduction and the consequent hypercortisolism that underlies the excess morbidity and mortality associated with Cushing disease. Preliminary data from an NIH-funded pilot phase 2 study indicate efficacy of oral seliciclib without conferring adrenal side effects seen with current medications used for this disease. The proposed expanded phase 2 multicenter trial has an adaptive design and will evaluate the safety and efficacy of two of three doses/schedules of seliciclib in patients with de novo or recurrent Cushing disease. Up to 30 subjects will be recruited, consented, and enrolled in consecutive dose cohorts through a collaborative effort among all five major specialty pituitary centers in greater Los Angeles. Results of this trial will lay the foundation for additional trials of this novel, highly targeted agent for treatment of this rare disease.